CLINICAL PHARMACOLOGY
Mechanism of Action
Pitavastatin competitively inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins.
Pharmacodynamics
In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, LIVALO was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum daily dose).
Pharmacokinetics
Absorption: Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single LIVALO doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of LIVALO with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC. The Cmax and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving 4 mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon.
Distribution: Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal.
Metabolism:. Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7).
Excretion: A mean of 15% of radioactivity of orally administered single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours.
Race: In pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.
Gender: In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of LIVALO in women in clinical studies.
Geriatric: In a pharmacokinetic study which compared healthy young and elderly (≥65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of LIVALO in elderly subjects in clinical studies.
Renal Impairment: In patients with moderate renal impairment (glomerular filtration rate of 30 to <60 mL/min/1.73 m2) and end stage renal disease receiving hemodialysis, pitavastatin AUC0-inf is 79 and 86% higher than those of healthy volunteers, respectively, while pitavastatin Cmax is 60 and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33 and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively. The effect of mild and severe renal impairment on pitavastatin exposure is unknown.
Hepatic Impairment: The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of pitavastatin Cmax between patients with moderate hepatic impairment (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of pitavastatin AUCinf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of pitavastatin Cmax between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of pitavastatin AUCinf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean pitavastatin t½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively.
Drug-Drug Interactions: The principal route of pitavastatin metabolism is glucuronidation via liver UGTs with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system.
Warfarin: The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the co-administration of LIVALO 4 mg daily. However, patients receiving warfarin should have their PT time or INR monitored when pitavastatin is added to their therapy.
Table 2. Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure
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*Data presented as x-fold change represent the ratio between co-administration and pitavastatin alone (i.e., 1-fold = no change). Data presented as % change represent % difference relative to pitavastatin alone (i.e., 0% = no change).
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†Considered clinically significant [see Dosage and Administration and Drug Interactions (7)] 　
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| Co-administered drug
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Dose regimen
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Change in
AUC*
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Change in Cmax*
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| Cyclosporine
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Pitavastatin 2 mg QD for 6 days + cyclosporine 2 mg/kg on Day 6
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↑ 4.6 foldâ€
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↑ 6.6 fold â€
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| Erythromycin
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Pitavastatin 4 mg single dose on Day 4 + erythromycin 500 mg 4 times daily for 6 days
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↑ 2.8 fold â€
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↑ 3.6 fold â€
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| Rifampin
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Pitavastatin 4 mg QD + rifampin 600 mg QD for 5 days
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↑ 29%
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↑ 2.0 fold
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| Atazanavir
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Pitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days
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↑ 31%
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↑ 60%
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| Gemfibrozil
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Pitavastatin 4 mg QD + gemfibrozil 600 mg BID for 7 days
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↑ 45%
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↑ 31%
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| Fenofibrate
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Pitavastatin 4 mg QD + fenofibrate 160 mg QD for 7 days
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↑18%
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↑ 11%
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| Ezetimibe
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Pitavastatin 2 mg QD + ezetimibe 10 mg for 7 days
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↓ 2%
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↓0.2%
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| Enalapril
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Pitavastatin 4 mg QD + enalapril 20 mg daily for 5 days
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↑ 6%
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↓ 7%
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| Digoxin
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Pitavastatin 4 mg QD + digoxin 0.25 mg for 7 days
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↑ 4%
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↓ 9%
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| Grapefruit Juice
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Pitavastatin 2 mg single dose on Day 3 + grapefruit juice for 4 days
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↑ 15%
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↓ 12%
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| Itraconazole
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Pitavastatin 4 mg single dose on Day 4 + itraconazole 200 mg daily for 5 days
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↓ 23%
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↓ 22%
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Table 3. Effect of Pitavastatin Co-Administration on Systemic Exposure to Other Drugs
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* Data presented as % change represent % difference relative to the investigated drug alone (i.e., 0% = no change).
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| Co-administered drug
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Dose regimen
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Change in
AUC*
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Change in Cmax*
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| Atazanavir
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Pitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days
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↑ 6%
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↑ 13%
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| Enalapril
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Pitavastatin 4 mg QD + enalapril 20 mg
daily for 5 days
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Enalapril
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↑ 12%
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↑ 12%
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| Enalaprilat
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↓ 1%
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↓ 1%
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| Warfarin
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Individualized maintenance dose of warfarin (2 - 7 mg) for 8 days + pitavastatin 4 mg QD for 9 days
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R-warfarin
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↑ 7%
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↑ 3%
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| S-warfarin
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↑ 6%
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↑ 3%
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| Ezetimibe
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Pitavastatin 2 mg QD + ezetimibe 10 mg for 7 days
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↑ 9%
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↑ 2%
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| Digoxin
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Pitavastatin 4 mg QD + digoxin 0.25 mg for 7 days
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↓ 3%
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↓ 4%
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| Rifampin
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Pitavastatin 4 mg QD + rifampin 600 mg QD for 5 days
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↓ 15%
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↓ 18%
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NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at 4 mg/day, there was an absence of drug-related tumors.
In a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the 4 mg/day maximum human dose.
In a 26-week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30, 75, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed.
Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested which also elicited high levels of cytotoxicity.
Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively, at systemic exposures 56- and 354-times clinical exposure at 4 mg/day based on AUC.
Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg/day (30-times clinical systemic exposure at 4 mg/day based on AUC) and higher during a fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15-times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed.
Animal Toxicology and/or Pharmacology
Central Nervous System Toxicity
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Wallerian degeneration has not been observed with pitavastatin. Cataracts and lens opacities were seen in dogs treated for 52 weeks at a dose level of 1 mg/kg/day (9 times clinical exposure at the maximum human dose of 4 mg/day based on AUC comparisons.
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